{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T19:59:18Z","timestamp":1775246358571,"version":"3.50.1"},"reference-count":89,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T00:00:00Z","timestamp":1736812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Bryostatin-1, a potent agonist of the protein kinase C, has been studied for HIV and cancer therapies. In HIV research, it has shown anti-HIV effects during acute infection and reactivation of latent HIV in chronic infection. As effective CD8+ T cell responses are essential for eliminating reactivated virus and achieving a cure, it is important to investigate how bryostatin-1 affects HIV-specific CD8+ T cells. HIV-specific CD8+ T cells often become exhausted, showing reduced proliferative potential and impaired cytokine production, a dysfunction also observed in cancer. Therefore, we further investigated how bryostatin-1 directly impacts exhausted CD8+ T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>PBMCs from people with HIV (PWH) were treated with bryostatin-1 and tracked with proliferation dye for cell expansion. One day 6, HIV-specific CD8+ T cells were detected by tetramers staining and examined by flow cytometry. By utilizing an established <jats:italic>in vitro<\/jats:italic> murine T cell exhaustion system, changes in inhibitory receptors, transcription factors, cytokine production and killing capacity of bryostatin-1 treated exhausted CD8+ T cells were determined by flow cytometry. RNA-seq analysis was performed to study transcriptional changes in these cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that bryostatin-1 improved the expansion and decreased PD-1 expression of HIV-specific CD8+ T cells. Bryostatin-1 enhanced the functionality and proliferation while decreasing inhibitory receptor expression of <jats:italic>in vitro<\/jats:italic> generated exhausted CD8+ T cells. Bryostatin-1 upregulated TCF-1 and decreased TOX expression. These changes were confirmed through RNA-seq analysis. RNA-seq revealed that mitogen-activated protein kinases (MAPK) 11 was significantly downregulated in exhausted CD8+ T cells, however, it greatly upregulated after bryostatin-1 treatment. Inhibition of MAPK11 in bryostatin-1-treated cells blocked the increased proliferation and IFN-\u03b3 production induced by bryostatin-1, but did not affect other bryostatin-1 induced effects, such as the reduction of inhibitory receptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our data demonstrate that bryostatin-1 induces a MAPK 11-dependent improvement in the proliferative and functional capacity of exhausted T cells. This study provides a rationale for bryostatin-1's potential to help eradicate the HIV reservoir during treatment, and it may also contribute to cancer immunotherapy by functionally improving exhausted CD8+ T cells.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1509874","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T05:10:55Z","timestamp":1736831455000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Bryostatin-1 enhances the proliferation and functionality of exhausted CD8+ T cells by upregulating MAP Kinase 11"],"prefix":"10.3389","volume":"15","author":[{"given":"Ling","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manzhi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marjan","family":"van Meurs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inge","family":"Brouwers-Haspels","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renske J. 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